The tachykinin neuropeptide substance P is a naturally occurring undecapeptide that stimulates contractile action on extravascular smooth muscle tissue upon binding with the receptor Neurokinin 1 (NK-1). NK-1 receptors inhibit the central nervous system (CNS) and peripheral tissues of humans. The interactions of substance P and NK-1 are frequently associated with inflammatory conditions, such as migraine, rheumatoid arthritis, asthma and inflammatory bowel disease. In addition, the modulation of Parkinson's disease and other disorders of the CNS and mediation of the emetic reflex are attributed to substance P/NK-1 contact.
NK-1 antagonists inhibit the interaction of substance P and NK-1 receptor site. These antagonists have previously been utilized for treatment of pain, headache, migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, edema, chronic inflammatory disease, asthma/bronchial hyperactivity, allergic rhinitis, inflammatory diseases of the gut, ocular injuries and ocular inflammatory disease. Such compounds are also believed to be useful in the treatment of various psychological disorders, including disorders of the CNS, as well as treatment of motion sickness, inducement of vomiting and reduction of cisplatin-induced emesis. See Stout, S. C., et al., Annu. Rev. Pharmacol. Toxicol. (2001) 41, 877, which is incorporated herein by reference in its entirety.
The conventional processes for synthesis of the pyridine ring structure of Roche's NK-1 antagonists require functionalization of a 2,5-disubstituted pyridine. One of the current methods for producing N-[6-(4-morpholinyl)-3-pyridinyl]pivalamide from 2-chloro-5-nitropyridine involves displacement of the chloro group with morpholine, reduction of the nitro group and acylation of the resulting amine by a pivaloyl group, such as pivaloyl chloride or pivaloyl anhydride. Regioselective lithiation of N-[6-(4-morpholinyl)-3-pyridinyl]pivalamide followed by reaction with an iodide source (such as iodine) then provides a 4-iodopyridine compound, which is used in a Suzuki coupling with an arylboronic acid. The coupled product is then hydrolyzed to remove the pivaloyl group. N-Methylation and acylation of the resulting aminopyridine compound then provides a 2,4,5-tri-substituted pyridine compound. See European Patent No. 1,103,545 (Ballard, T. M. et al.), which is incorporated herein by reference in its entirety. The cost of this process is relatively high due to the need for lithiation. In addition, this process requires production of nitropyridine, which presents a safety hazard.
Another process for producing pyridine ring system based NK-1 receptor agonist utilizes Hoffman rearrangement reaction of a nicotinamide compound. In this process, microbial oxidation of nicotinic acid is used to produce 6-hydroxynicotinic acid, which is then converted to 6-chloronicotinic acid. The carboxylic acid group is then converted to a tert-butylamide group by converting the carboxylic acid to an acid chloride and reacting the acid chloride with tert-butylamine. The resulting pyridine compound is then reacted with o-tolylmagnesium chloride, followed by an oxidation of the resulting product to produce a 4-(o-tolyl)substituted pyridine compound. The overall yield of this process is often low, and requires an excess amount of o-tolylmagnesium chloride. In addition, an oxidation reaction is required to regenerate the pyridine ring system. Removal of the tert-butyl group followed by Hoffman rearrangement of the amide group results in a formation of an isocyanate which is then trapped with methanol to yield a carbamate. The overall production cost of this process is high due to use of expensive starting materials. And furthermore, the overall production efficiency of this process is low due to variability in the success of the Grignard reaction.
Additional known methods for producing pyridine compounds include the Hantzsch, Kröhnke and Guareschi-Thorpe syntheses. Preparation of pyridine compounds via the Guareschi-Thorpe synthesis uses cyanoacetamide and an arylacetate (e.g., ethyl benzoylacetate) as starting materials. See U.S. Pat. No. 4,182,887, issued to Roch, J. et al., which is incorporated herein by reference in its entirety. This process results in a low yield (42%) of 2,6-dihydroxy-3-cyano-4-phenylpyridine with bezoylacetate and still a lower yield when an aryl group is ortho-substituted.
Trans-4-Aryl-3-cyano-6-ox-5-pyridino-1,4,5,6-tetrahydropyridin-2-olates can also be prepared by reaction of a pyridinium salt, an aromatic aldehyde and ethyl cyanoacetate in the presence of a base. See, e.g., Shestopalov, A. M., et al. Synthesis (1991) 402; Shestopalov, A. M., et al. Khim. Geterotsikl. Soedin. (1990) 363; and Litvinov, V. P., Shestopalov, A. M. Zh. Org. Khim. (1997) 33, 975, which are incorporated herein by reference in their entireties.
Another suitable starting material for the production of the NK-1 antagonist pyridine derivative is an amide of the formula:
This acetamide compound can be obtained in good yield by the reaction of 2-chloroacetamide with pyridine. See Katritzky, A. F., et al. J. C. S. Perkins I(1981) 1180–1185.
Regioselective displacement of chloride from the 2,6-dichloro-3-cyanopyridine by an amine and the conversion of the nicotinonitrile to a nicotinamide are well known to one skilled in the art. In general, unhindered primary amines attack at the 2-position, while hindered primary and secondary amines attack at the 6-position. See U.S. Pat. No. 4,061,642, issued to Fleckenstein, E et al., and U.S. Pat. No. 3,853,895, issued to Lamm, G. and Dehnert, J., which are incorporated herein by reference in their entireties. Hydrolysis of a nicotinonitrile to a nicotinamide compound can be achieved using a variety of reagents, including sulfuric acid, aqueous hydroxide, basic hydrogen peroxide or potassium trimethylsilanolate. See, e.g., Miyamoto, T., et al. Het. Chem. (1987) 24, 1333; Salem, M., et al. Heterocycles (2000) 53, 1129; Humphries, M., Ramsden, C., Sythesis (1999) 985; Merchant, K., Tet. Lett. (2000) 41, 3747, all of which are incorporated herein by reference in their entireties.
While methods are available for the production of pyridine derivatives, there exists a need for a pyridine compound production process that utilizes low cost starting materials. There is also a need for a process that avoids the shortcoming of the Grignard reaction's variability.